PROJECT SUMMARY Full Research Project 2 - Nicotine Dependence and Lung Cancer Genetics in African Americans TUFCCC: Camille Ragin, PhD (Leader) HC: Joel Erblich, PhD (Leader) Despite substantial public health efforts to promote smoking cessation, a significant racial difference in the burden of lung cancer persists. African Americans (AA) consistently have a higher incidence of lung cancer compared to Whites. Notably, AA smokers are at increased risk of lung cancer despite the fact that they typically smoke fewer cigarettes per day than Whites. Research has demonstrated that both lung cancer and nicotine dependence have strong familial and genetic components, and numerous genetic polymorphisms have been identified as contributing to risk of developing these conditions. Substantial racial differences in the association of genetic variants with nicotine metabolism have been reported and strong preliminary evidence exists that AAs are more likely to be poor metabolizers of tobacco smoke carcinogens, thus predisposed to greater risk of developing lung cancer. We will, for the first time, systematically explore whether ancestry informative markers (AIMs) in genes involved in tobacco metabolism and addiction predispose AA smokers to poor metabolic capacity and greater addiction to tobacco. Leveraging an existing cohort of AA smokers, we will 1) investigate the role of these AIMs in both tobacco metabolism and nicotine dependence and 2) test the motivational effects of genetic feedback, in two clinical and community samples in two major urban areas: Philadelphia (n=180) and New York City (n=180). Aim 1 will identify associations between AIMs putatively related to the tobacco metabolism and detoxification and actual metabolic/detoxification capacity in AA smokers, Aim 2 will identify associations between AIMs putatively related to addiction pathways and measures of nicotine dependence among AA smokers, and Aim 3 will test the possibility that genetic feedback about increased lung cancer risk associated with AA ancestry may influence perceived risk, cancer worry, acute psychological distress, and motivation to quit smoking. The PIs have unique, yet complementary areas of expertise in behavioral and genetic factors associated with cigarette smoking and tobacco-related disease. The proposed study integrates both of these areas of expertise, providing interdisciplinary synergy to yield high impact results that will not only benefit the investigators, but will have the potential to inform future basic, translational, and clinical research on enhancing cancer health equity. The collective work generated by this study will provide novel data that will guide two unique, but complementary, areas of future investigation: (a) a tailored intervention to promote smoking cessation among AA and (b) future studies of mechanistic processes involving the role of ancestry informative genetic markers in tobacco-related disease susceptibility and addiction in AA. This study will provide a unique opportunity, not only to explore novel hypotheses about the genetics of lung cancer risk in AA smokers, but also to support the overall collaboration and training objectives of the U54. The PIs will have the opportunity to continue their research and mentoring work collaboratively, and leverage their complementary expertise to address timely, cutting-edge questions of cancer health equity.